The discovery of thromboxane A.sub.2 (TxA.sub.2) and prostacyclin (PGI.sub.2), has increased the understanding of vascular haemostasis. Platelets transform arachidonic acid initially into prostaglandin endoperoxides, via an enzyme, cyclooxygenase, and subsequently into TxA.sub.2, by an enzyme, thromboxane synthetase. TxA.sub.2 is a potent vasoconstrictor and proaggregatory substance, and as such, its actions are directly opposed to PGI.sub.2. When platelets are stimulated by thrombin, collagen, ADP and adrenaline, the platelets release and metabolise endogenous arachidonic acid to TxA.sub.2. This endogenous TxA.sub.2 appears to play an essential role in a second irreversible phase of ADP- and collagen- induced platelet aggregation. In addition to aggregating platelets, TxA.sub.2 is a potent vasoconstrictor and thus the continuous generation of TxA.sub.2 by platelets adhering to damaged arterial walls results in localised vasoconstriction of the arteries.
PGI.sub.2 is a powerful vasodilator and potent anti-aggregatory agent, effective in preventing platelets from aggregating and in reversing platelet aggregation by dissipating platelet clumps. PGI.sub.2 is synthesised from prostaglandin endoperoxides by an enzyme, prostacyclin synthetase, located in the endothelial layer of blood vessels and in circulating polymorphonuclear leukocytes.
Normal morphological interaction between platelets and vessel walls provides for the transfer of prostaglandin endoperoxides from platelets to endothelial cells thereby increasing PGI.sub.2 production and preventing platelet deposition on vessel walls. Thus when endothelial prostacyclin synthetase is inactivated, for example, by lipid peroxides, or when endothelium becomes detached exposing the underlying connective tissues (i.e., collagen) to platelets, or when polymerising fibrin prevents the interaction between platelets and endothelial cells, arterial thrombosis may develop.
Thus, TxA.sub.2 has been implicated as a causative agent in thrombus formation, myocardial infarction, stroke, variant angina and peripheral vascular disease. Effective in vivo inhibition of platelet thromboxane synthetase is likely to be beneficial for two major reasons: (i) TxA.sub.2 formation in response to platelet aggregatory stimuli is blocked, reducing platelet reactivity and vascular spasm, and (ii) increased availability of prostaglandin endoperoxides as a substrate for prostacyclin synthetase increases the production of the platelet inhibitory and vasodilator PGI.sub.2 in the blood and vessel wall. Therefore, the PGI.sub.2 /TxA.sub.2 balance is shifted decisively in favour of PGI.sub.2.
A PGI.sub.2 /TxA.sub.2 imbalance is also believed to be a contributory factor in migraine. The migraine headache is associated with a pre-headache reduction of cerebral blood flow followed by dilatation in both the intra- and extra-cerebral vascular areas during the headache phase. Prior to the headache, blood levels of 5-hydroxytryptamine are elevated, suggesting the occurrence of in vivo aggregation and release of the amine from the platelet stores. Migraine sufferers also tend to have hyperactive blood-platelets and it has been postulated that an abnormality of platelet function is not only a major factor in the pathogenesis of migraine attacks but a primary cause (E. Hanington, Lancet, (1978), 8084, 501). Therefore selective inhibition of thromboxane synthetase may be beneficial in migraine therapy.
Platelets obtained from some patients with diabetes mellitus are hyperactive, exhibiting enhanced in vitro TxA.sub.2 generation and aggregation when stimulated by a variety of aggregatory agents. Such patients have a high frequency of vascular complications such as retinopathy, coronary heart disease and peripheral arterial occlusive disease. A PGI.sub.2 /TxA.sub.2 imbalance is probably responsible for the microvascular complications of diabetes and consequently a thromboxane synthetase inhibitor may have clinical utility in the therapy of these complications.
Aspirin and other non-steroidal anti-inflammatory drugs (e.g. indomethacin, sulphinpyrazone) inhibit the enzyme cyclooxygenase and therefore inhibit PGI.sub.2 production as well as TxA.sub.2 production. A drug which specifically inhibits TxA.sub.2 formation while leaving PGI.sub.2 biosynthesis unimpaired, should therefore display advantages in the treatment of conditions involving an imbalance of PGI.sub.2 /TxA.sub.2 over the currently available cyclooxygenase inhibitors.
U.S. Pat. No. 4,243,671 describes the use of 1-(3-phenyl-2-propenyl)-1H-imidazole and its hydrochloride salt as an inhibitor of thromboxane synthetase and as an inhibitor of arachidonic acid-induced platelet aggregation and bronchoconstriction.